Great strides have been made in the management of lymphoma with therapies tailored to particular cell types, e.g., those expressing the B cell surface molecule CD20. Monoclonal antibodies and radioimmunoconjugates such as [131I]Tositumomab (Bexxar) and [90Y]ibritumomab iuxetan (Zevalin) have led to therapeutic successes with less therapy-associated morbidity and mortality. Nevertheless, lymphoma is the cause of death for at least 20,000 people annually in the US, providing impetus for the search for new approaches to target tumor cells selectively. Since its discovery in association with Burkitt's lymphoma, Epstein-Barr Virus (EBV) has been found in association with a variety of lymphomas and other tumors, including gastric and nasopharyngeal carcinoma. Some of these lymphomas are among the very most refractory to standard therapies. Nasal-type NK lymphoma, EBV-associated peripheral T cell lymphoma and EBV-associated Hodgkin's lymphoma in older patients stand out from other lymphomas for their aggressive courses. We propose a radionuclide-based therapy for EBV-associated malignancies that relies on the metabolic concentration of a radiolabeled low molecular weight substrate in tumors mediated by the EBV thymidine kinase (TK). The approach that we will employ is also in analogy with ganciclovir-based gene therapy, except that we can omit the gene tagging step because tumor cells harboring the EBV genome will already possess the TK that we can harness for targeted, enzymatic radiotherapy. Because the substrate specificity for the viral TK is orthogonal to that of cellular TK, we can use a radiotherapeutic version of the virus-specific TK substrate, 2'-fluoro-2'-deoxy-1-2-D-arabinofuranosyl-5-iodouracil (FIAU), to effect this therapy. Because the viral genome is latent, it must be activated using a pharmacologic inducer such as bortezomib. We have already successfully administered [124I]FIAU to patients with infection for imaging non-cellular (bacterial) TK and have already determined, from a library of over 3,000 tested compounds, that bortezomib (Velcade) was most potent at activating the viral lytic cycle, and therefore TK, within infected cells. We have recently shown in animal models that Bortezomib-induced Enzyme-Targeted Radiotherapy (BETR) was capable of halting the progression of or eliminating EBV-associated tumors. Here we will translate this promising experimental technique to the clinic by performing careful dosimetry studies, using FIAU-PET, which will be used to guide an initial therapeutic study in lymphoma. We anticipate that this enzyme-mediated molecular radiotherapy, which we will use here to treat herpesvirus-associated tumors, will encourage further investigation into the activation of tissue-specific enzymes for cancer imaging and therapy.